The recent obesity epidemic, which affects more women than men worldwide, is a major risk factor for hypertension and the cause of a three-fold increase in the prevalence of hypertension in young adult women. Despite decade of research investigating the mechanisms regulating blood pressure, millions of women remain inadequately treated for hypertension largely due to a lack of understanding of the sex-specificity of the mechanisms regulating blood pressure. In preliminary studies for this proposal, we have made major observations that shed significant new light on this issue. The first is that obesity-induced hypertension in females progresses differently from males and involves leptin-mediated increases in plasma aldosterone. Blockade of aldosterone disproportionately lowers blood pressure in obese female mice versus males. The second observation is the potential identification of novel site and regulator of aldosterone secretion. Human, rodent, and cell evidence indicate that leptin exerts a direct control of aldosterone secretion in adrenal glands and adipose tissue. The last observation is that leptin-induced aldosterone secretion is potentiated in females, by the presence of estrogen. Indeed, estrogen removal with ovariectomy abolishes the correlation between leptin and aldosterone. In the current proposal, we will rigorously test these concepts in three aims. The first aim will combine the use of pathophysiological models of obesity with a novel leptin receptor antagonist to identify the mechanisms regulating blood pressure in obese female mice. The second aim will employ pharmacological and cellular approach to determine the role of estrogen in leptin-mediated aldosterone secretion. The third aim will purse these concepts, in vivo, testing whether estrogen removal abolishes the aldosterone dependence of the mechanisms regulating blood pressure in obese female mice. Taken together these studies will provide new information on the sex-specificity of the mechanisms regulating blood pressure and will likely identify a new signaling pathway leading to the synthesis of aldosterone. Successful completion of these aims may identify new therapeutic strategies for obesity-related hypertension in women and provide the proof of principle required for sex-based clinical trials of therapeutic strategies to treat obesit-induced hypertension.